2,5-Benzodiazocine derivatives and salts thereof, as well as pharmaceutical agent comprising as effective component at least one of the derivatives and salts

ABSTRACT

A 2,5-benzodiazocine derivative represented by a formula ##STR1## wherein R 1  is phenyl or p-methoxyphenyl, R 2  is hydrogen or methyl, and R 3  is p-methoxyphenethyl, 3-(p-fluorobenzoyl)-propyl, cyclopropylmethyl or ##STR2## or a salt of such novel compound as well as a CNS-active pharmaceutical agent containing as an effective component at least one of said derivatives and salts.

The present invention relates to a novel 2,5-benzodiazocine derivative and a salt thereof, as well as a pharmaceutical agent comprising as effective component at least one of the derivatives and salt.

The derivative is represented by a formula ##STR3## wherein R₁ is phenyl or p-methoxyphenyl, R₂ is hydrogen or methyl, and R₃ is p-methoxyphenethyl, 3-(p-fluorobenzoyl)-propyl, cyclopropylmethyl or ##STR4##

The compounds represented by the formula I and salts thereof show various actions on the nervous system, particularly analgetic, cough curing, antipyretic and sleep depth increasing actions and thus are useful as analgetics, cough cures, antipyretics and sedatives.

The compounds shown by the formula I are novel ones which have not been disclosed in any prior art literature and according to the invention, can be prepared by starting with, for instance, a 1-substituted or unsubstituted phenyl-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine represented by the formula ##STR5## wherein R₁ has the meaning as referred to, converting the 5-hydrogen into an organic radical in a manner known per se, such as the acid chloride method, carboxylic acid method, alkylhalogenide method and the like, and if necessary methylating 2-hydrogen in a manner known per se. A suitable protective radical may selectively be used for the methylation in 2-position.

The following compounds can be listed as exemplary ones among the compounds shown by the formula I.

(a) 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-2,5-benzodiazocine ##STR6## (b) 5-(p-methoxyphenethyl)-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-2,5-benzodiazocine ##STR7## (c) 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-phenyl-2-methyl-2,5-benzodiazocine ##STR8## (d) 5-cyclopropylmethyl-1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine ##STR9## (e) [5(E)]-ethyl-4-[[4-[2-(1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocin)-5-yl]ethyl]phenyl]amino-4-oxo-2-butenoate ##STR10## (f) 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine ##STR11##

The compounds shown by the formula I and pharmaceutically acceptable salts thereof can be administered by injection, orally or by any conventional route. A dosage for the purpose of medical treatment for an adult varies depending on dosing route and times but is about 5 to 200 mg per day and for instance, in oral dosage, 30 to 40 mg per time is preferable for an adult.

The invention will now be further explained in detail, with reference to Examples.

EXAMPLE 1 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-2,5-benzodiazocine (compound I-a) (hydrochloride)

200 g (745.3 mmol) of 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine, 190 g (776.5 mmol) of 4,4-ethylenedioxy-4-(p-fluorophenyl)-butyl chloride, 80 g (952.3 mmol) of NaHCO₃ and 1.5 liter of dimethylformamide were stirred at 100° C. for 4 hours and then the solvent was removed under a reduced pressure. The reaction product was extracted with ethyl ether, washed with water, dried on Na₂ SO₄. The solvent was distilled off and then the resulting oily substance was refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) to obtain 253 g (71.3%) of an intermediate as oily substance.

To a mixture of 53 g (111.2 mmol) of this oily substance, 16.7 g (165.2 mmol) of triethylamine and 60 mg of CHCl₃, 100 ml CHCl₃ solution of 13.3 g (122.6 mmol) of ClCOOC₂ H₅ was added in dropwise for 1 hour at room temperature and under inert gas atmosphere and after completion of the addition, the resulting solution was further stirred for 1 hour. The resulting reaction mixture was washed with water, dried on Na₂ SO₄, and subjected to distillation to remove the solvent. The remaining oily substance was dissolved in 1 liter of ethyl ether, ice-cooled to add 17.5 g of LiAlH₄ and then refluxed for 4.5 hours under stirring. The reaction mixture was cooled and 70 ml of 0.8 N-NaOH was added thereto to cause a decomposition of the catalyzer. A forming precipitate was filtered off. The filtrate was washed with CH₂ Cl₂ and subjected to distillation under a reduced pressure. The remaining oily substance was refined through a silica gel column chromatography (CH₂ Cl₂ -ethyl ether) to obtain 47 g of an oily substance. The oily substance was dissolved in 350 ml of methanol, 375 ml of 2 N-HCl were added thereto and then the resulting solution was stirred at room temperature for 1 hour to obtain 33.2 g of forming crystals. The filtrate was concentrated under a reduced pressure, made into alkali state with ammonia, extracted with CH₂ Cl₂, dried, subjected to distillation to remove the solvent, and then the remaining oily substance was separated and refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) and converted in methanol into its hydrochloride to obtain 8 g thereof in the form of crystal. These crystals were combined (total 41.7 g, yield 52.9%) and then recrystallized from water/ethanol/methylethylketone to obtain the objective compound (chloride) as colorless prism crystals having melting point of 188°-194° C. (dec.). This salt may be made into free base, in a conventional manner.

Elementary Analysis: C₂₈ H₃₁ FN₂ O₂.2HCl.1/2H₂ O; Cal. C 63.35, H 6.48, N 5.30; Found C 63.47, H 6.48, N 5.39.

IR (ν_(max) ^(KBr)) cm⁻¹ :

2550 (>N.sup.⊕ <), 1680 (>═O)

MS:

EI/DI (m/z); 446 (M⁺), 252 (base)

CI/DI (i-Bu) (m/z); 447 (M+1)

High MS (m/z); C₂₈ H₃₁ FN₂ O₂ (M⁺)

Cal. 446, 2369

Found 446, 2374

NMR (CDCl₃) δ ppm:

8.1-7.78 (2H, m, 2,6-positions of benzoyl, Ar--H)

7.4-6.7 (10H, m, Ar--H)

5.2 (1H, s, C1-H)

4.0 (2H, s, C6-H)

3.72 (3H, s, OCH₃)

3.18-1.83 (10H, m, Methylene-H excepting C6)

2.28 (3H, s, N--CH₃)

EXAMPLE 2 5-[3-(p-methoxyphenethyl)]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-benzodiazocine (Compound I-b) (hydrochloride)

To a mixture of 80.0 g (298.5 mmol) of 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine, 42.1 g (416.1 mmol) of triethylamine and 1.2 liter of CHCl₃, 250 ml CHCl₃ solution of 57.8 g (313.3 mmol) of p-methoxyphenyl-acetyl chloride were added in dropwise for 1.5 hours at internal temperature of -30° C. and under inert gas atmosphere and then the mixture was further stirred at 0° C. for 1 hour. Thereafter the resulting reaction mixture was washed with water, dried on Na₂ SO₄ and subjected to distillation to remove the solvent.

The remaining oily substance was dissolved in 69 g (1.499 mol) of formic acid. To the solution kept at 60° C. under stirring on water bath, 51 g (0.595 mol) of 35% formaldehyde were added in dropwise for 20 minutes. After completion of the addition, the water bath was removed and then the mixture was further stirred for 30 minutes.

The reaction mixture was poured onto ice blocks, made into an alkali state with use of conc. NH₄ OH, extracted with CH₂ Cl₂, washed with water, dried on Na₂ SO₄ and then subjected to distillation to remove the solvent. The remaining oily substance was separated and refined through a silica gel column chromatography (CH₂ Cl₂ -ethyl ether) to obtain 112 g (87.3%) of an amide.

112 g of the amide were dissolved in 400 ml of anhydrous tetrahydrofuran and the resulting solution was added in dropwise at room temperature for 1.5 hours under inert gas atmosphere into 1.2 liters ethyl ether suspension of 30 g of LiAlH₄ and then the resulting mixture was refluxed for 1 hour. While ice-cooling the mixture, 130 ml of 0.8 N-NaOH were added to decompose the catalyzer and then filtered to remove a formed precipitate. The filtrate was washed with ethyl acetate/CH₂ Cl₂ and concentrated under a reduced pressure. The remaining oily substance was separated and refined through a silica gel column chromatography (CH₂ Cl₂ -ethyl acetate) to obtain 84.0 g (67.6%) of a light yellowish oily substance. The substance was converted into hydrochloride in methanol in a conventional manner and recrystallized from methanol/methylethylketone to obtain the objective compound (hydrochloride) as colorless prism crystals having melting point of 198°-204° C. This salt can be converted into free base in a conventional manner.

Elementary Analysis: C₂₇ H₃₂ N₂ O₂.2HCl; Cal. C 66.25, H 7.00, N 5.72; Found C 66.30, H 7.15, N 5.82.

IR (ν_(max) ^(KBr)) cm⁻¹ :

2820 (OCH₃), 2560 (>N.sup.⊕ <), 1250 (--O--)

MS:

EI/DI (m/z); 416 (M⁺), 240 (base)

CI/DI (i-Bu) (m/z); 417 (M+1)

High MS (m/z); C₂₇ H₃₂ N₂ O₂ (M⁺)

Cal. 416, 2461

Found 416, 2433

NMR (CDCl₃) δ ppm:

7.45-6.75 (12H, m, Ar--H)

5.21 (1H, s, C1-H)

4.07 (2H, s, C6-H)

3.75 (3H, s, OCH₃)

3.1-2.7 (8H, m, methylene-H)

2.25 (3H, s, N--CH₃)

EXAMPLE 3 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-phenyl-2-methyl-2,5-benzodiazocine (Compound I-c) (hydrochloride)

50 g (0.21 mol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine, 56 g (0.23 mol) of 4,4-ethylenedioxy-4-(p-fluorophenyl)-butyl chloride, 26.5 g (0.315 mol) of NaHCO₃ and 373 ml of dimethylformamide were stirred at 100° C. for 4 hours and then subjected to distillation under a reduced pressure to remove the solvent. To the remaining substance, ethyl ether/water was added to extract the reaction products which was washed with water and dried on Na₂ SO₄. The solvent therein was distilled off and then the remaining oily substance was separated and refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/15) to obtain 76 g of an oily substance.

To a mixture of 4.00 g (8.97 mmol) of the oil, 1.18 g (11.7 mmol) of triethylamine and 100 ml of CHCl₃, 30 ml CHCl₃ solution of 1.07 g (9.87 mmol) of ClCOOC₂ H₅ were added in dropwise for 1 hour, while stirring under inert gas atmosphere. The reaction mixture was washed with water, dried on Na₂ SO₄ and subjected to distillation under a reduced pressure to remove the solvent. The remaining oily substance was dissolved in a mixture of 300 ml of ethyl ether and 100 ml of tetrahydrofuran and in the solution, 4 g of LiAlH₄ were added at 0° C. under inert gas atmosphere. The mixture was refluxed for 4 hours, while stirring same under inert gas atmosphere and then ice-cooled to add 0.8 N-NaOH for causing decomposition of the catalyzer. The reaction mixture was filtered to remove a formed precipitate. The filtrate was washed with ethyl acetate/CHCl₃ and condensed under a reduced pressure. The remaining oily substance was dissolved in methanol, 100 ml of 3 N-HCl were added thereto and then the mixture was stirred at room temperature for 15 minutes. Thereafter the solution was made into an alkali state by adding ammonia, extracted with CHCl₃, washed with water, dried on Na₂ SO₄, subjected to distillation under a reduced pressure to remove the solvent and then refined through a silica gel column chromatography (triethylamine/ethyl ether/n-hexane=1/1/10) to obtain 2.42 g (52.6%) of substantially colorless oily substance.

The oil was treated by hydrogen chloride in methanol to convert the same into hydrochloride and recrystallized from 5% water/methanol/methylethylketone to obtain the objective compound (hydrochloride) as colorless prism crystals having melting point of 186°-192° C. (dec.). The salt may be converted into free base in a conventional manner.

Elementary Analysis: C₂₇ H₂₉ FN₂ O.2HCl; Cal. C 66.26, H 6.38, N 5.72; Found C 65.88, H 6.59, N 5.42.

IR (ν_(max) ^(KBr)) cm⁻¹ :

2450 (NH⁺), 1680 (C═O)

MS:

EI/DI (m/z); 416 (M⁺), 210 (base)

CI/DI (i-Bu) (m/z); 417 (M+1)

High MS (m/z); C₂₇ H₂₉ FN₂ O (M⁺)

Cal. 416, 2264

Found 416, 2272

NMR (CDCl₃) δ ppm:

8.2-7.8 (2H, m, C2', 6'-H)

7.6-6.6 (11H, m, Ar--H)

5.26 (1H, s, C1-H)

4.02 (2H, s, C6-H)

3.3-1.8 (10H, m, --CH₂ and NCH₂ CH₂ CH₂ --)

2.28 (3H, s, N--CH₃)

EXAMPLE 4 5-cyclopropylmethyl-1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine (Compound I-d) (hydrochloride)

To a mixture of 72.5 g (304.2 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine, 56 ml (d≃0.72, 398.4 mmol) of triethylamine and 1 liter of CHCl₃, 220 ml CHCl₃ solution of 35 g (334.8 mmol) of cyclopropanecarbonylchloride were added in dropwise for 1.5 hours at internal temperature of -30° C., while stirring under inert gas atmosphere. Thereafter, the mixture was further stirred at 0° C. for 1 hour and then washed with water, dried on Na₂ SO₄ and distilled off the solvent therefrom.

The remaining oily substance was dissolved in 400 ml of anhydrous tetrahydrofuran and the resulting solution was added in dropwise for 1.5 hours at room temperature and under inert gas atmosphere into 1.2 liter ethyl ether suspension of 30 g of LiAlH₄ to reflux the mixture for 1 hour. The reaction mixture was ice-cooled and 130 ml of 1 N-NaOH were added thereto to decompose the catalyzer. After having filtered off a formed precipitate, the filtrate was washed with ethyl acetate/CH₂ Cl₂ and concentrated under a reduced pressure. The remaining oily substance was refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) to obtain 83 g (93.3%) of a light yellowish oily substance. The oil was treated by hydrogen chloride in methanol and crystallized from 3% water/methanol/methylethylketone to obtain the objective compound (hydrochloride) as colorless prism crystals having melting point of 234° to 240° C. (dec.). This salt may be converted into free base in a conventional manner.

Elementary Analysis: C₂₀ H₂₄ N₂.2HCl1/4H₂ O; Cal. C 64.95, H 7.22, N 7.57; Found C 64.87, H 7.18, N 7.51.

IR (ν_(max) ^(KBr)) cm⁻¹ :

2700, 2600 (NH⁺)

MS:

MI/DI (m/z); 292 (M⁺), 221 (base)

CI/DI (i-Bu) (m/z); 293 (M+1)

High MS (m/z); C₂₀ H₂₄ N₂ (M⁺)

Cal. 292, 1936

Found 292, 1929

NMR (CDCl₃) δ ppm:

7.6-6.6 (9H, m, Ar--H)

5.55 (1H, s, C1-H)

4.26 (2H, ABq, J=13.0 Hz, Δν=20 Hz, C6-H₂)

3.2-2.0 (6H, m, --CH₂ -- and ##STR12## 1.77 (1H, s, NH, disappear by adding D₂ O) 1.3-0.0 (5H, m, ##STR13##

EXAMPLE 5 [5(E)]-ethyl-4-[[4-[2-(1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine)-5-yl]ethyl]phenyl]amino-4-oxo-2-butenoate (Compound I-e) (hydrochloride)

A mixture of 8.00 g (33.6 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine, 8.51 g (37.0 mmol) of p-nitrophenethylbromide, 4.23 g (50.4 mmol) of NaHCO₃ and 60 ml of dimethylformamide was stirred at 100° C. for 10 hours under inert gas atmosphere and then subjected to distillation to remove the solvent therein. After having added 150 ml of water, the reaction mixture was extracted with CHCl₃, washed with water, dried on Na₂ SO₄, subjected to distillation to remove the solvent and refined through a silica gel column chromatography (ethyl ether/n-hexane=1/1-triethylamine/ethyl ether=1/10) to obtain 10.5 g (80.7%) of nitrophenethyl compound. 5.54 g (14.3 mmol) of this compound were dissolved in 25 ml of CHCl₃ and 150 ml of methanol were added therein. After having added 1 g of 10% Pd-C under inert gas atmosphere, the mixture was stirred at room temperature for 3 hours under hydrogen gas atmosphere and then filtered off the catalyst. The filtrate was concentrated under a reduced pressure, treated by hydrogen chloride in methanol to form hydrochloride and then recrystallized same from methanol/methylethylketone to obtain 6.60 g (99.0%) of aminophenethyl compound as colorless prism crystals having melting point of 252°-258° C. (dec.).

2.93 g (8.21 mmol) of free base of compound were dissolved in 100 ml of tetrahydrofuran and then 30 ml tetrahydrofuran solution of 1.47 g (9.03 mmol) of ethyl-3-(chloroformyl)acrylate was added therein in dropwise for 30 minutes at 0° C. After having stirred 1 hour, the reaction mixture was concentrated under a reduced pressure and 100 ml of water were added thereto. The solution was made into alkali state with ammonia, extracted with CHCl₃, washed with water, dried over Na₂ SO₄, subjected to distillation to remove the solvent and refined through a silica gel column chromatography (triethylamine/ethyl acetate/n-hexane=0.5/1/5-0.3/2/1) to obtain 2.97 g (74.8%) of the objective compound (free base). The free base was treated by hydrogen chloride in methanol and recrystallized from water/methanol/methylethylketone to obtain the desired compound (hydrochloride) as colorless prism crystals having melting point of 248°-255° C. (dec.). This salt may also be converted into the free base in a conventional manner.

Elementary Analysis: C₃₀ H₃₃ N₃ O₃.2HCl; Cal. C 64.75, H 6.34, N 7.55; Found C 64.52, H 6.49, N 7.26.

IR (ν_(max) ^(KBr)) cm⁻¹ :

2480 (NH⁺), 1700, 1675 (C═O)

MS:

EI/DI (m/z); 483 (M⁺), 194 (base)

CI/DI (i-Bu) (m/z); 484 (M+1)

High MS (m/z); C₃₀ H₃₃ N₃ O₃ (M⁺)

Cal. 483, 2522

Found 483, 2534

NMR (CDCl₃) δ ppm:

8.40 (1H, br, NH--CO, disappear by adding D₂ O)

7.7-6.6 (15H, m, Ar--H and olefinic proton)

5.53 (1H, s, C1-H)

4.28 (1H, ABq, J=13.0 Hz, Δν=20 Hz, C6-H₂)

4.25 (2H, q, J=7.0 Hz, --CH₂ CH₃)

3.2-2.5 (8H, m, --CH₂ -- and NCH₂ CH₂ Ar)

1.93 (1H, br-s, NH, disappear by adding D₂ O)

1.30 (3H, t, J=7.0 Hz, --CH₂ CH₃)

EXAMPLE 6 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine (Compound I-f)

10.72 g (39.95 mmol) of 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine, 10.27 g (41.97 mmol) of 4,4-ethylenedioxy-4-(p-fluorophenyl)-butyl chloride, 4.2 g (50.00 mmol) of NaHCO₃ and 250 ml of dimethylformamide were stirred at 145° C. for 4 hours and then the solvent was distilled off. After having added 30 ml of CH₂ Cl₂ and 300 ml of ethyl ether, filtered off insoluble materials and distilled off the filtrate, the remaining oily substance was refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) to obtain 15.8 g (83.0%) of the objective compound (free base) as substantially colorless oil. To the oil, 450 ml of methanol, 180 ml of water and 60 ml of conc. HCl were added, refluxed for 1 hour with stirring, distilled off the solvent and then the residue was recrystallized from water/ethanol to obtain 16.5 g (81.7%) of the desired compound (hydrochloride) as colorless prism crystals having melting point of 217°-234° C. (dec.). The salt may also be converted into the free base in a conventional manner.

Elementary Analysis: C₂₇ H₂₉ FN₂ O₂.2HCl; Cal. C 64.16, H 6.18, N 5.54; Found C 64.31, H 6.31, N 5.55.

IR (ν_(max) ^(KBr)) cm⁻¹ :

2700-2600 (>N.sup.⊕ <), 1685 (C═O)

MS:

EI/DI (m/z); 432 (M⁺), 251 (base)

CI/DI (i-Bu) (m/z); 433 (M+1)

High MS (m/z); C₂₇ H₂₉ FN₂ O₃ (M⁺)

Cal. 432, 2211

Found 432, 2185

NMR (CDCl₃) δ ppm:

8.3-7.72 (2H, m, 2,6 positions in benzoyl)

7.5-6.68 (10H, m, Ar--H)

5.42 (1H, br-s, C1-H)

4.16 (2H, ABq, J=12.6 Hz, Δν=21.0 Hz, C6-H)

3.65 (3H, s, OCH₃)

3.18-2.35 (8H, m, ##STR14## 2.35-1.8 (2H, m, ##STR15## 1.65 (1H, br-s, NH, disappear by adding D₂ O)

Physical Properties of Other Salts

(1) 2.fumarate of Compound I-a

Crystalline form: colorless prism crystal;

Melting point: 164°-168° C. (dec.)

Elementary Analysis: C₂₈ H₃₁ FN₂ O₂.2C₄ H₄ O₄ ; Cal. C 63.70, H 5.79, N 4.13; Found C 63.71, H 5.85, N 4.16.

(2) 1,5-naphthalenedisulfonate of Compound I-a

Melting point: 205°-208° C. (dec.)

Elementary Analysis: C₂₈ H₃₁ FN₂ O₂.C₁₀ H₈ S₂ O₆.H₂ O; Cal. C 60.62, H 5.49, N 3.72; Found C 60.23, H 5.37, N 3.80.

(3) 2.fumarate of Compound I-c

Crystalline form: colorless prism crystal

Melting point: 149°-153° C. (dec.)

Elementary Analysis: C₂₇ H₂₉ FN₂ O.2C₄ H₄ O₄ ; Cal. C 64.81, H 5.75, N 4.32; Found C 64.66, H 5.80, N 4.37.

(4) 1,5-naphthalenedisulfonate of Compound I-c

Melting point: 230°-234° C. (dec.)

Elementary Analysis: C₂₇ H₂₉ FN₂ O.C₁₀ H₈ S₂ O₆.H₂ O; Cal. C 59.99, H 5.58, N 3.78; Found C 60.26, H 5.40, N 3.94.

Pharmaceutical Tests

(A) Analgetic Action

(i) Haffner's Method

In accordance with a usual manner, dd-male mice of 14 to 22 g were classified into groups, each having 10 mice, compounds to be tested in various concentrations were given to each mouse and then clamped a tail root of the mouse with use of Koffer clamps in each time period of having lapsed 15, 30, 45 and 60 minutes from the dosage to measure an analgetic action of the compounds by judging as "negative" when the tested mouse cries or looks back.

Further the number of deaths was counted in each 10 mice group after having lapsed 2 hours from dosage of each testing agent into abdominal cavity and then ED₅₀, LD₅₀ and 95% confidence limit were calculated based on the Richfield and Wilcoxson Methods to compare the results obtained on the agents.

(ii) Acetic Acid Stretching Method

The dd-male mice of 17 to 23 g were classified into groups, each having 10 mice, and 0.7% aqueous solution of acetic acid was dosed into abdominal cavity for each mouse in a ratio of 10 ml/kg and then a stretching condition was observed over 5 minutes of having lapsed 10 to 15 minutes from the dosage. The test was repeated 4 times to obtain total measured value and an inhibition ratio was measured from number of stretching actions. A judgement has been given in "Yes" or "No" system.

According to the Richfield and Wilcoxson Methods, ED₅₀, LD₅₀ and 95% confidence limit were calculated and compared the same for each testing agents and Control.

Each testing agent and control was orally given 30 minutes before the dosage of the acetic acid in a ratio of 100 mg/10 ml/kg.

(B) Cough Curing Action

To each Hartley type guinea pig of 300 to 450 g, 0.5 ml/kg of menbutal was dosed into abdominal cavity to lightly anesthetize. Thereafter, the trachea was exposed by a throat surgical operation and a pin-hole was formed therein so as to allow an insertion of a hog bristle therein. The guinea pigs who have a cough in each time when the bristle was inserted into the pin-hole after having lapsed 5 and 20 minutes from the surgical operation were employed for the test. Measurements of the cough curing action were carried out in each time of having lapsed 30, 45, 60, 90 and 120 minutes from a dosage of agents to be tested into abdominal cavity in a ratio of 2.5 ml/kg (50 mg/kg). An inhibition ratio was determined based on total measured value in 6 times tests and a value measured before the dosage.

The inhibition ratio was classified into following 5 stages.

    ______________________________________                                         (-)       Inhibition Ratio 0%                                                  (±)    "                0-10%                                               (+)       "                10-20%                                              (++)      "                20-35%                                              (+++)     "                more than 35%                                       ______________________________________                                    

(C) Antipyretic Action

Wister type male rats of 100 to 140 g were classified into groups, each having 4 to 5 rats. The rats were abstrained from food for 1 day and then each rat was entered in each cage. The body temperature was measured under a constant room temperature through the rectum. This body temperature measurement was carried out in 3 times before a dosage of agents as well as after lapsed 30, 60, 90, 120 and 150 minutes from the dosage.

Judgements have been given based on following 5 measures.

(-) clearly showing no decrease in the body temperature,

(±) there is found a decrease in the body temperature but a notifiable difference can not be recognized,

(+) decrease in the body temperature is by 1.5° C. and obtained at least one result showing a notifiable difference of P<5%, or the decrease in the body temperature is by 1° C. only but show the value of P<1%,

(++) showing decrease of 1° to 2° C. and obtaining at least one result of a notifiable difference of P<1%,

(+++) showing decrease of 2° to 3° C. and obtaining at least one result of a notifiable difference of P<0.1%.

(D) Effect on Sleep

The dd-type male mice of 16 to 24 g were classified into groups, each having 10 mice. To each mouse, a testing agent was dosed through abdominal cavity and after having lapsed 30 minutes from the dosage, 40 mg/kg of pentobarbital was also dosed through abdominal cavity to measure a time of sleeping period. The sleeping time in question designates a time period, wherein a facing reflex disappears. Judgements were given based on following 7 measures.

(---) sleeping time was shortened by 60 minutes or more in comparison with control,

(--) sleeping time was shortened by 30 to 60 minutes in comparison with control,

(-) sleeping time was shortened by 10 to 30 minutes in comparison with control,

(±) sleeping time was shortened or extended by ±10 minutes in comparison with control,

(+) sleeping time was extended by 10 to 30 minutes in comparison with control,

(++) sleeping time was extended by 30 to 60 minutes in comparison with control,

(+++) sleeping time was extended by 60 minutes or more in comparison with control.

(E) Acute Toxity

The dd-type 5 weeks male mice of 21 to 26 g and Wister type 5 weeks male rats of 110 to 150 g were classified into groups, each having 10 mice or rats. After having given testing agents to the mice and rats, general conditions, number of deaths in each day and body weight changes have been observed over 7 days. An LD₅₀ value was calculated based on total number of deaths during the 7 days testing time period, in accordance with the Richfield-Wilcoxson Method. The surviving animals were dissected to visually observe internal organs thereof.

The following table shows results obtained through the tests as given above.

The agents according to the invention employed for the tests were hydrochlorides of the identified compounds.

    __________________________________________________________________________                                Cough                                                                          Curing   Antipyretic                                Analgetic Action           Action   Action                                     Compounds                                                                            Acetic Acid          in       in                                         or    Stretching                                                                               Haffner's  abdominal                                                                               abdominal                                  agents                                                                               Method    Method     cavity   cavity                                     (Example                   50       25  50                                     No.)        ED.sub.50  ED.sub.50                                                                          mg/Kg    mg/Kg                                                                              mg/Kg                                  __________________________________________________________________________     I-a   24.3 ˜                                                                         40.5                                                                               13.2 ˜                                                                          18.4                                                                               ++           ++                                     (1)   67.5      25.8                                                           I-b   31.7 ˜                                                                         48.5                                                                               20.2 ˜                                                                          26.2                                                                               +            ++                                     (2)   74.2      34.1                                                           I-c   1.6 ˜                                                                          5.7 29.6 ˜                                                                          44.2                                                                               +            ++                                     (3)   20.1      66.0                                                           I-d   8.6 ˜                                                                          13.5                                                                               11.7 ˜                                                                          17.1                                                                               --           ++                                     (4)   21.3      25.0                                                           I-e   32.6 ˜                                                                         61.1                                                                               52.7 ˜                                                                          80.3                                                                               --           ++                                     (5)   114.4     122.4                                                          I-f   6.2 ˜                                                                          11.5                                                                               22.7 ˜                                                                          30.7                                                                               --           ++                                     (6)   21.4      41.6                                                           Nefopam                    ++       ++                                         (Control)                  (25                                                                            mg/Kg)                                              __________________________________________________________________________     Sleep                                                                          Incrementing                                                                   Action                                                                         Compounds in    Acute Toxity (mg/Kg)                                           or    Oral                                                                               abdominal                                                                            Rat         Mouse                                              agents                                                                               dosage                                                                             cavity     Intravenous Intravenous                                                                           in                                     (Example                                                                             100 50    Oral injectional                                                                           Oral injectional                                                                           abdominal                              No.)  mg/Kg                                                                              mg/Kg dosage                                                                              dosage dosage                                                                              dosage cavity                                 __________________________________________________________________________     I-a   +++ ++    3500 20.0   1500 30.1   178.8                                  (1)                  (19.3 ˜                                                                              (28.7 ˜                                                                         (159.1 ˜                                              20.7)       31.5)  201.0)                                 I-b   +++ +++   4090 20.7   623  33.0   124.4                                  (2)             (3298 ˜                                                                       (19.1 ˜                                                                         (560.3 ˜                                                                      (31.9 ˜                                                                         (114.4 ˜                                         5072)                                                                               22.4)  692.8)                                                                              34.2)  135.2)                                 I-c   +++ +++   >4000                                                                               23.8   1700 29.0   207.8                                  (3)                  (22.4 ˜                                                                         (1250 ˜                                                                       (26.8 ˜                                                                         (179.6 ˜                                              25.3)  2312)                                                                               31.4)  240.4)                                 I-d   --  --    485  17.8   215  18.0   51.6                                   (4)             (391 ˜                                                                        (16.8 ˜                                                                         (180.7 ˜                                                                      (16.7 ˜                                                                         (48.4 ˜                                          601) 18.8)  255.9)                                                                              19.5)  55.0)                                  I-e   ++  --    >5000                                                                               --     938  --     >200                                   (5)                         (751 ˜                                                                   1172)                                              I-f   +++ +++   2890 19.8   340  35.9   108.9                                  (6)             (2388 ˜                                                                       (19.1 ˜                                                                         (291.1 ˜                                                                      (32.5 ˜                                                                         (102.8 ˜                                         3497)                                                                               20.5)  397.1)                                                                              39.7)  115.4)                                 Nefopam                                                                              --  --    595  18.0   356  36.8   72.4                                   (Control)                                                                            (50 (25   (492 ˜                                                                        (16.5 ˜                                                                         (306 ˜                                                                        (33.6 ˜                                                                         (69.5 ˜                                mg/Kg)                                                                             mg/Kg)                                                                               720) 19.6)  414) 40.3)  75.4)                                  __________________________________________________________________________

PHARMACEUTICAL AGENT PREPARING EXAMPLE 1 Tablets for oral dosage

    ______________________________________                                         (1) Compound I-a (hydrochloride)                                                                       40     (mg)                                            (2) Mannitol            100                                                    (3) Starch              100                                                    (4) Carboxymethylcellulose calcium                                                                     10                                                     (5) Polyvinylpyrrolidone                                                                               50                                                     (6) Magnesium stearate  3                                                      ______________________________________                                    

The components 1 to 3 and 5 were mixed and the component 4 dissolved in ethanol was added and mixed therewith. The resulting mixture was made granules by a granulating machine and after having dried the same, the component 6 was added and mixed therewith and then finally made into each 300 mg tablet by a punch having diameter of 10 mm.

The tablet can be dosed as it was but if necessary, a conventional easily soluble coating may be applied thereon.

PHARMACEUTICAL AGENT PREPARING EXAMPLE 2 Injectionally dosing agent

Compound I-a was dissolved in distilled water in a ratio of 15 mg/2.5 ml, filtered under a sterilized condition, filled in each ampule by 2 ml, each ampule fused closed and then sterilized at 130° C. for 40 minutes. 

What is claimed is:
 1. A 2,5-benzodiazocine derivative represented by a formula ##STR16## wherein R₁ is phenyl or p-methoxyphenyl, R₂ is hydrogen or methyl, and R₃ is methoxyphenethyl, 3-(p-fluorobenzoyl)-propyl, cyclopropylmethyl or ##STR17## or a salt thereof.
 2. A compound as claimed in claim 1, selected from the group consisting of ##STR18## or a salt of the compound.
 3. A pharmaceutical agent which comprises as an effective component at least one 2,5-benzodiazocine derivative represented by the formula ##STR19## wherein R₁ is phenyl or p-methoxyphenyl, R₂ is hydrogen or methyl, and R₃ is methoxyphenethyl, 3-(p-fluorobenzoyl)-propyl, cyclopropylmethyl radical or ##STR20## or salts of said derivatives.
 4. The pharmaceutical agent as claimed in claim 3, wherein said effective component is at least one of the compounds represented by formulae ##STR21## or a salt of said compound. 